DESCRIPTION: This proposal is aimed at evaluating the hypothesis that bcl-2 inhibition of apoptosis is mediated by increased levels of glutathione (GSH). The LY-as lymphoma cell line, which readily undergoes apoptosis in response to chemotherapeutic agents and ionizing radiation, will be transfected with bcl-2 under control of the inducible lac promoter. Antisense phosphorothioate oligonucleotides will be used to reduce bcl-2 expression in the LY-ar cell line which expresses high levels of bcl-2 and is resistant to induction of apoptosis. The relationship between GSH levels and apoptosis will be characterized in both systems. The mechanisms responsible for higher levels of GSH in cells resistant to apoptosis will be delineated and the role of reactive oxygen species (ROS) as mediators of apoptosis and GSH scavenging will be further defined. Animal models using the LY-as and LY-ar cell lines will be used to evaluate strategies with buthionine sulfoximine (BSO) to lower GSH to increase sensitivity to apoptosis.